Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](C1C=CC(C[O:9][C:10]([CH2:12][S:13][C:14]2[CH2:15][C@@H:16]3[CH:33]([CH:34]([OH:36])[CH3:35])[C:32](=[O:37])[N:17]3[C:18]=2[C:19]([O:21]CC2C=CC([N+]([O-])=O)=CC=2)=[O:20])=[O:11])=CC=1)([O-])=O.C(=O)(O)[O-].[Na+:44]>O1CCOCC1.C(O)C.O.[Pd]>[C:10]([CH2:12][S:13][C:14]1[CH2:15][C@@H:16]2[CH:33]([CH:34]([OH:36])[CH3:35])[C:32](=[O:37])[N:17]2[C:18]=1[C:19]([O-:21])=[O:20])([OH:11])=[O:9].[Na+:44].[Na+:44].[C:10]([CH2:12][S:13][C:14]1[CH2:15][C@@H:16]2[CH:33]([CH:34]([OH:36])[CH3:35])[C:32](=[O:37])[N:17]2[C:18]=1[C:19]([O-:21])=[O:20])([OH:11])=[O:9]
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SCC(=O)OCc3ccc([N+](=O)[O-])cc3)C[C@H]12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Solvent: O
Product: CC(O)C1C(=O)N2C(C(=O)[O-])=C(SCC(=O)O)C[C@H]12

Procedure:
A solution of crude p-nitrobenzyl 2-(p-nitrobenzyloxycarbonyl)methylthio-6-(1-hydroxy)ethyl-carbapen-2-em-3-carboxylate (8.7 mg) in dioxane (1.20 ml) is diluted with ethanol (0.10 ml) and water (0.70 ml) containing sodium bicarbonate (2.3 mg). The resulting solution is treated with 10% palladium on charcoal (15 mg) and hydrogenated at 40 psi for 60 minutes. The mixture is diluted with water to 5 ml and centrifuged to remove the catalyst which is washed with more water (2×1 ml). The combined aqueous solution is washed with ethyl acetate (4×3 ml), filtered through a cotton plug, concentrated in vacuo to ca. 1 ml, and lyophilized to provide the title compound as a solid: UV (pH 7 phosphate buffer) 301 nm; electrophoresis (0.05 M pH 7 phosphate buffer 2 KV, 20 ma, 20 mins) gives a biactive zone migrating 9.3 cm toward the anode (dicarboxylate).
Reaction SMILES: Cl.Cl.Cl.[CH3:4][C:5]1[N:9]([CH:10]2[CH2:16][C@H:15]3[N:17]([CH2:18][CH2:19][C:20]4([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[O:25][CH2:24][CH2:23][NH:22][CH2:21]4)[C@H:12]([CH2:13][CH2:14]3)[CH2:11]2)[C:8]2[CH:32]=[CH:33][CH:34]=[CH:35][C:7]=2[N:6]=1.CCN(CC)CC.[CH3:43][C:44]([CH3:49])([CH3:48])[C:45](Cl)=[O:46]>C(Cl)Cl>[CH3:43][C:44]([CH3:49])([CH3:48])[C:45]([N:22]1[CH2:23][CH2:24][O:25][C:20]([CH2:19][CH2:18][N:17]2[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[CH2:16][CH:10]([N:9]2[C:8]4[CH:32]=[CH:33][CH:34]=[CH:35][C:7]=4[N:6]=[C:5]2[CH3:4])[CH2:11]3)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:21]1)=[O:46]
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccccc2)CNCCO1
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccccc2)CN(C(=O)C(C)(C)C)CCO1
Reaction time: 24 h
Yield: 107.7 %

Procedure:
To a solution of 2-methyl-1-{(1R,5S)-8-[2-(2-phenylmorpholin-2-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole trihyrdochloride (65 mg, 0.11 mmol) and Et3N (0.08 mL, 0.55 mmol in 1 mL CH2Cl2 was added trimethylacetyl chloride (0.02 mL, 0.17 mmol), and the reaction was stirred for 24 h. After washing with saturated aqueous NaHCO3, the organic phase was isolated, dried (Na2SO4), concentrated and chromatographed (5% (2M NH3/MeOH) in CHCl3) to afford 1-((1R,5S)-8-{2-[4-(2,2-dimethylpropanoyl)-2-phenylmorpholin-2-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole (61 mg, quant.) as a film: 1H NMR (400 MHz, CDCl3), δ 7.68 (m, 1H), 7.45-7.40 (m, 2H), 7.38-7.27 (m, 3H), 7.19-7.11 (m, 2H), 4.77-4.63 (m, 2H), 3.76-3.54 (m, 4H), 3.40-3.20 (m, 3H), 2.59 (s, 3H), 2.48-2.36 (m, 2H), 2.15-1.85 (m, 8H), 1.69-1.59 (m, 2H), 1.19 (s, 9H); ESI-MS 515 (M+H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:5]=1[CH2:6][O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][C@H:11]1[CH2:23][CH3:24])=[O:9].[CH3:30]I.[ClH:32]>CN(C=O)C>[ClH:32].[F:3][C:4]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:5]=1[CH2:6][O:7][C:8]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][C@H:11]1[CH2:23][CH3:24])=[O:9]
Reactant: CI
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1cc(O)ccc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@H]1CNCCN1C(=O)OCc1cc(OC)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
A mixture of 6.27 mg (0.157 mmol) NaH (60% suspension in mineral oil) and 40 mg (0.105 mmol) (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester 1-(2-fluoro-5-hydroxy-benzyl) ester in 1 ml DMF was stirred for 30 min at room temperature under argon. 16.4 mg (0.115 mmol) methyliodide was added and the mixture was stirred 30 min at room temperature. After addition of 60 ul HCl (37%) the mixture was purified with preparative HPLC eluting with an acetonitrile/water gradient. The fractions containing the desired intermediate were combined and 0.05 ml HCl (37%) was added before evaporation to dryness. The residue was taken up in 1 ml dioxane and 0.15 ml HCl (37%) and stirred for 30 min at 60° C. Evaporation of the mixture yielded 20 mg (57%) of the title compound. MS (ISP): 297 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:33])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:17]=[C:16]2[CH3:32])=[CH:7][CH:6]=1)C.[OH-].[Na+].Cl>CCO.O>[CH3:32][C:16]1[N:15]([CH2:14][CH2:13][CH2:12][O:11][C:8]2[CH:7]=[CH:6][C:5]([C:4]([OH:33])=[O:3])=[CH:10][CH:9]=2)[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:18]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:17]=1
Reactant: CCOC(=O)c1ccc(OCCCn2c(C)nc(-c3ccccc3)c2-c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nc(-c2ccccc2)c(-c2ccccc2)n1CCCOc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
(Scheme 2 (I)) To a solution of 4-[3-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-propoxy]-benzoic acid ethyl ester (0.80 g, 1.8 mmol) in EtOH (20 mL) was added NaOH (10 N, 4.0 mL, 40.0 mmol). The resulting mixture was stirred at rt for 3 hours, diluted with water, acidified to pH˜1 using 1N HCl, extracted by CH2Cl2, and then was dried over MgSO4. After filtration and concentration in vacuo, the residue was purified by flash chromatography (SiO2: MeOH/CH2Cl2). This compound was obtained as a white dry foam in HCl salt form (0.80 g, 1.8 mmol, 99% yield): 1H NMR (DMSO): δ1.93 (m, 2H), 2.67 (s, 3H), 3.97 (t, 2H), 4.13 (t, 2H), 6.85 (d, J=8.82 mHz, 2H), 7.33 (s, 5H), 7.43 (m, 2H), 7.55 (m, 3H), 7.86 (d, J=8.82 mHz, 2H), 12.64 (b, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:14])[C:6](=[C:10]([O:12][CH3:13])[CH:11]=1)[C:7]([OH:9])=[O:8].[C:15](Cl)(Cl)=[O:16]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[NH:14][C:15](=[O:16])[O:9][C:7](=[O:8])[C:6]2=[C:10]([O:12][CH3:13])[CH:11]=1
Reactant: O=C(Cl)Cl
Reactant: COc1cc(N)c(C(=O)O)c(OC)c1
Product: COc1cc(OC)c2c(=O)oc(=O)[nH]c2c1

Procedure:
4,6-Dimethoxyisatoic anhydride is prepared from 4,6-dimethoxyanthranilic acid (H. Newman & R. Anzier, J. Org. Chem. 34, 3484 (1969)) and phosgene according to the method of E. C. Wagner and M. F. Fegley, Org. Synthesis 27, 45 (1947).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH:13]1[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][CH2:14]1)[CH:6]=[CH:5]2.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]=1>>[O:15]1[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH:13]([NH:12][C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:30])[F:32])[N:24]=4)[CH:3]=3)[N:8]=2)[CH2:14]1
Reactant: Nc1cccc(C(F)(F)F)n1
Reactant: Brc1ccc2nc(NC3COc4ccccc43)ccc2c1
Product: FC(F)(F)c1cccc(Nc2ccc3nc(NC4COc5ccccc54)ccc3c2)n1

Procedure:
The title compound, light yellow foam, MS: m/e=423.2 (M+H+), was prepared in accordance with the general method of example 66 from rac-(6-bromo-quinolin-2-yl)-(2,3-dihydro-benzofuran-3-yl)-amine (see example 96, step A) and commercially available 2-amino-6-trifluoromethyl-pyridine.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.[N+:23]([C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1)([O-:25])=[O:24].C(N(CC)CC)C>CN(C=O)C.ClCCl>[N+:1]([C:4]1[CH:12]=[C:11]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]([O:8][C:29]1[CH:30]=[CH:31][C:26]([N+:23]([O-:25])=[O:24])=[CH:27][CH:28]=1)=[O:7])([O-:3])=[O:2]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
A 100-mL 2-necked round bottom flask was fitted with thermometer, magnetic stirrer, and reflux condenser with nitrogen bypass. The flask was charged with 1.23 g (5 mmol) of 2-nitro-4-(methylsulfonyl)benzoic acid, 2 drops of DMF, and 20 mL of dichloromethane. Oxalyl chloride (0.70 g, 5.5 mmol) was added dropwise and the mixture was stirred for 1 hr. A solution consisting of 0.70 g (5 mmol) of 4-nitrophenol, 0.55 g (5.5 mmol) of triethylamine and 5 mL of dichloromethane was added and the mixture was stirred for 1 hr. The mixture was diluted with 100 mL of dichloromethane, washed twice with 100 mL portions of aqueous sodium bicarbonate, once with 100 mL of water, dried with magnesium sulfate, filtered, and volatiles removed under reduced pressure to give the title product as 1.56 g of off-white solid, m.p. 171-173° C. 1H NMR (CDCl3): δ 3.19 (s, 3), 7.47 (m, 2), 8.10 (m, 1), 8.38 (m, 3), 8.69 (m, 1).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:20])[NH:4][C:5](=[O:19])[N:6]([C@H:8]2[C@@:12]([F:14])([CH3:13])[C@H:11]([OH:15])[C@@:10]([F:18])([CH2:16][OH:17])[O:9]2)[CH:7]=1.C([Mg]Cl)(C)(C)C.Cl[C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]=1[O:38][P:39](=[N:41][C@@H:42]([CH3:49])[C:43]([O:45][CH:46]([CH3:48])[CH3:47])=[O:44])=[O:40].CO>C1COCC1>[CH:46]([O:45][C:43](=[O:44])[C@@H:42]([N:41]=[P:39]([O:38][C:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:36]=[CH:37][C:28]=1[O:17][CH2:16][C@:10]1([F:18])[C@@H:11]([OH:15])[C@:12]([F:14])([CH3:13])[C@H:8]([N:6]2[CH:7]=[C:2]([Br:1])[C:3](=[O:20])[NH:4][C:5]2=[O:19])[O:9]1)=[O:40])[CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)OC(=O)[C@H](C)N=[P+]([O-])Oc1c(Cl)ccc2ccccc12
Reactant: C[C@]1(F)[C@H](n2cc(Br)c(=O)[nH]c2=O)O[C@](F)(CO)[C@H]1O
Agent: CC(C)(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)OC(=O)[C@H](C)N=[P+]([O-])Oc1c(OC[C@@]2(F)O[C@@H](n3cc(Br)c(=O)[nH]c3=O)[C@](C)(F)[C@@H]2O)ccc2ccccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 53 %

Procedure:
To a solution of chiral 5-bromo-1-((2R,3R,4S,5S)-3,5-difluoro-4-hydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-1H-pyrimidine-2,4-dione (50 mg, 0.14 mmol) prepared in Preparation 7 in THF (3 ml) at 0° C. was added a THF solution (Aldrich, 1 M) of tert-butylmagnesium chloride (0.35 mL, 0.35 mmol) dropwise. The mixture was stirred at 0° C. for 15 min, followed by the addition of THF solution (0.5 M) of (2S)-isopropyl 2-(chloro(naphthalen-1-yloxy)phosphorylamino)propanoate prepared in Example 2 Step B (0.7 mL, 0.35 mmol). The reaction mixture was warmed to room temperature and stirred for 2 h. Methanol (2 mL) was added to quench the reaction. The mixture was purified by flash chromatography (5-10% MeOH in DCM) to give (S)-2-[[(2S,3S,4R,5R)-5-(5-bromo-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2,4-difluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(naphthalen-1-yloxy)-phosphorylamino]-propionic acid isopropyl ester as a white solid (50 mg, 52%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O>>[N:21]1([CH2:20][CH2:19][O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5]([C:4]3[CH:3]=[C:2]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[F:30])[CH:29]=[CH:28][CH:27]=3)=[O:6])=[CH:9][CH:10]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: OB(O)c1ccccc1F
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(Br)c1
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(-c2ccccc2F)c1

Procedure:
Compound is prepared from 3-bromo-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-benzamide and 2-fluorophenyl boronic acid according to conditions described in general procedure K. 1H NMR 300 MHz (CDCl3) δ 8.3 (d, 1H), 8.15 (s, 1H), 7.18-8.05 (m, 11H), 6.8 (d, 1H, J=10 Hz), 4.3 (t, 2H), 3.75 (m, 4H), 3.0 (t, 2H), 2.6 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[CH:7]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:6][CH2:5][C:4]=2[C:3]=1[C:18]#[N:19].[CH3:20][C:21]1[C:29]2[CH2:28][O:27][C:26](=[O:30])[C:25]=2[CH:24]=[CH:23][C:22]=1[CH:31]1[CH2:33][O:32]1>CCO>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[CH:7]([CH2:11][N:12]3[CH2:13][CH2:14][N:15]([CH2:33][CH:31]([OH:32])[C:22]4[CH:23]=[CH:24][C:25]5[C:26](=[O:30])[O:27][CH2:28][C:29]=5[C:21]=4[CH3:20])[CH2:16][CH2:17]3)[CH2:6][CH2:5][C:4]=2[C:3]=1[C:18]#[N:19]
Reactant: N#Cc1c(F)ccc2c1CCC2CN1CCNCC1
Reactant: Cc1c(C2CO2)ccc2c1COC2=O
Solvent: CCO
Product: Cc1c(C(O)CN2CCN(CC3CCc4c3ccc(F)c4C#N)CC2)ccc2c1COC2=O
Temperature: 120 °C

Procedure:
5-Fluoro-1-(piperazin-1-ylmethyl)-2,3-dihydro-1H-indene-4-carbonitrile (60 mg, 0.23 mmol), 4-methyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one (88 mg, 0.46 mmol), were added to a 5 mL microwave tube containing a stir bar; to the mixture was added EtOH (2.5 mL). The tube was capped, degassed and purged with N2. It was then placed in a microwave reactor and heated at 120° C. for 1 hour; LC indicated formation of some desired product. The tube was again placed in a microwave reactor and heated again at 150° C. for 30 min; LC indicated formation of more product. The solution was concentrated to dryness, re-dissolved in DCM (20 mL) and was then absorbed into silica gel. It was then loaded onto a silica column for separation with the solvent system of (10% MeOH in DCM), to give 5-fluoro-1-({4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}methyl)-2,3-dihydro-1H-indene-4-carbonitrile. LC-MS (IE, m/z): 450 [M+1]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([OH:28])[CH:6]=[CH:7][C:8]=1[C:9]1[N:13]([CH3:14])[C:12]([C:15]([CH3:27])([O:17][C:18]2[C:23]([F:24])=[CH:22][C:21]([F:25])=[CH:20][C:19]=2[F:26])[CH3:16])=[N:11][N:10]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][C:37]([NH2:39])=[O:38].O>CN(C=O)C>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[C:9]1[N:13]([CH3:14])[C:12]([C:15]([CH3:16])([O:17][C:18]2[C:23]([F:24])=[CH:22][C:21]([F:25])=[CH:20][C:19]=2[F:26])[CH3:27])=[N:11][N:10]=1)[O:28][CH2:36][C:37]([NH2:39])=[O:38]
Reactant: Cn1c(-c2ccc(O)cc2Cl)nnc1C(C)(C)Oc1c(F)cc(F)cc1F
Reactant: NC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(-c2ccc(OCC(N)=O)cc2Cl)nnc1C(C)(C)Oc1c(F)cc(F)cc1F
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
3-chloro-4-{4-methyl-5-[1-methyl-1-(2,4,6-trifluorophenoxy)ethyl]-4H-1,2,4-triazol-3-yl}phenol monohydrochloride (40 mg) was suspended in DMF (2 ml), potassium carbonate (64 mg) and 2-bromoacetamide (26 mg) were added thereto, followed by stirring at 60° C. for 30 minutes. The reaction solution was cooled to room temperature, water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine in this order and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=100:1 to 100:5). The resulting residue was dissolved in ethyl acetate, 4M hydrogen chloride-ethyl acetate (1 ml) was added thereto and the solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate to obtain 2-(3-chloro-4-{4-methyl-5-[1-methyl-1-(2,4,6-trifluorophenoxy)ethyl]-4H-1,2,4-triazol-3-yl}phenoxy}acetamide monohydrochloride (17 mg), as a white solid.
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[SH:15][C:16]1[N:17]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]([C:31]#[N:32])=[CH:23][CH:22]=2)[CH:18]=[CH:19][N:20]=1>ClCCl>[C:31]([C:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21]([N:17]2[CH:18]=[CH:19][N:20]=[C:16]2[S:15][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:22][CH:23]=1)#[N:32]
Reactant: N#Cc1ccc(-n2ccnc2S)c2ccccc12
Reactant: CCOC(=O)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CSc1nccn1-c1ccc(C#N)c2ccccc12
Reaction time: 3 h

Procedure:
Triethylamine (4.92 mL, 35.32 mmol), followed by ethyl bromoacetate (3.74 mL, 33.72 mmol) were added to a stirring slurry of 4-(2-mercapto-1H-imidazol-1-yl)-1-naphthonitrile (8.07 g, 32.11 mmol) in dichloromethane (60 mL) and stirring continued for 3 h. The mixture was washed with aqueous HCl solution (0.2M 100 mL), 50% saturated sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated. Hexanes (100 mL) were added and the mixture concentrated to provide ethyl 2-(1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetate as a light-tan solid (10.47 g, (97%).
Reaction SMILES: Br.Br.C[N:4]([CH:15]1[CH2:20][CH2:19]NCC1)[C:5]1[S:6][C:7]2[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:8]=2[N:9]=1.[C:21](=[O:24])([O-:23])[O-].[Na+].[Na+].Cl[CH2:28][CH2:29][CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1>CN(C)C(=O)C>[C:12]([OH:14])(=[O:32])/[CH:13]=[CH:7]\[C:21]([OH:23])=[O:24].[F:39][C:36]1[CH:37]=[CH:38][C:33]([O:32][CH2:31][CH2:30][CH2:29][CH2:28][N:4]2[CH2:5][CH2:19][CH:20]([CH2:15][NH:4][C:5]3[S:6][C:7]4[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:8]=4[N:9]=3)[CH2:20][CH2:15]2)=[CH:34][CH:35]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc(OCCCCCl)cc1
Reactant: CN(c1nc2ccc(O)cc2s1)C1CCNCC1
Agent: Br
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=C(O)/C=C\C(=O)O
Product: Oc1ccc2nc(NCC3CCN(CCCCOc4ccc(F)cc4)CC3)sc2c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 117.8 %

Procedure:
A mixture of 2-(methyl-4-piperidinylamino)-6-benzothiazolol dihydrobromide (0.056 mol) and sodium carbonate (0.142 mol) in N,N-dimethylacetamide (500 ml) was stirred for 1 hour at 60° C. A solution of 1-(4-chlorobutoxy)-4-fluorobenzene (0.061 mol) in N,N-dimethylacetamide (15 ml) was added and the reaction mixture was stirred overnight at 60° C. The cooled reaction mixture was poured out into ice water. This mixture was extracted with toluene. The separated organic layer was dried (MgSO4), filtered and the solvent was evaporated. The residue (30 g) was purified by column chromatography over silica gel (eluent: CH2 Cl2 /CH3OH 97/3). The pure fractions were collected and the solvent was evaporated. The residue was converted into the (Z)-2-butenedioic acid salt (1:1) in 2-propanol. The precipitate was filtered off and dried, yielding 18 g (58.9%)of 2-[[1-[4-(4-fluorophenoxy)butyl]-4-piperidinyl]methylamino]-6-benzothiazolol (Z)-2-butenedioate(1:1); mp. 180.7° C. (comp. 4).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:8][CH:9]([OH:13])[CH2:10][CH:11]=[CH2:12].C(N(CC)CC)C.C(#N)C>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2](/[CH:12]=[CH:11]/[CH2:10][CH:9]([OH:13])[CH3:8])[CH:3]=1
Reactant: C=CCC(C)O
Reactant: Brc1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CC(O)C/C=C/c1cccnc1
Temperature: 140 °C
Yield: 96.8 %

Procedure:
A mixture of 3-bromopyridine (7.50 g, 47.46 mmol), 4-penten-2-ol (4.90 g, 56.96 mmol), palladium(II) acetate (106 mg, 0.47 mmol), tri-o-tolylphosphine (575 mg, 1.89 mmol), triethylamine (28.4 mL, 204.11 mmol) and acetonitrile (25 mL) was heated in a sealed glass tube at 140° C. for 14 h. The reaction mixture was cooled to ambient temperature, diluted with water, and extracted with chloroform (3×200 mL). The combined chloroform extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation to give a pale-yellow oil (7.50 g, 81.0%).
Reaction SMILES: [CH3:1][N:2]([O:23][CH3:24])[C:3](=[O:22])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].[CH:25](I)([CH3:27])[CH3:26].[C:29](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][N:2]([O:23][CH3:24])[C:3](=[O:22])[C:4]1[CH:9]=[C:8]([O:10][CH2:26][CH:25]([CH3:27])[CH3:29])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: O=C([O-])[O-]
Reactant: CC(C)I
Reactant: CON(C)C(=O)c1cc(O)ccc1NC(=O)OCc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)c1cc(OCC(C)C)ccc1NC(=O)OCc1ccccc1

Procedure:
A solution of N-methyl-N-methyloxy-2-benzyloxycarbonylamino-5-hydroxybenzamide (3.0 g), isopropyl iodide (2.2 g) and potassium carbonate (2.0 g) in N,N-dimethylformamide (20 ml) was stirred for 15 hours at 70° C. To the reaction mixture was added water, which was subjected to extraction with ethyl acetate (80 ml). The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by means of a silica gel column chromatography to give N-methyl-N-methyloxy-2-benzyloxycarbonylamino-5-isobutyloxybenzamide.as an orange oily product (1.0 g).
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH2:7][CH2:6][CH:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:3]1.[H-].[Na+].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=1[C:28]([F:31])([F:30])[F:29].O>C1COCC1>[F:29][C:28]([F:30])([F:31])[C:19]1[CH:20]=[C:21]([C:24]([F:27])([F:25])[F:26])[CH:22]=[CH:23][C:18]=1[CH2:17][N:8]1[C:2](=[O:1])[CH2:3][CH2:4][CH:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:7]1
Reactant: CCOC(=O)C1CCNC(=O)CC1
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1CCC(=O)N(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reaction time: 0.08 h
Yield: 68.6 %

Procedure:
To a solution of ethyl 7-oxoazepane-4-carboxylate (9.78 g) in THF (250 mL) was added 60% sodium hydride (2.33 g, containing mineral oil) under ice-cooling. The reaction mixture was stirred for 5 min under ice-cooling, and 1-(bromomethyl)-2,4-bis(trifluoromethyl)benzene (17.9 g) was added. The reaction mixture was stirred at room temperature overnight, water was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (14.9 g).
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.C(N(CC)CC)C.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][NH2:35])[CH:24]=1>CN(C)C=O>[Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([NH:35][CH2:34][CH2:33][O:32][CH2:31][CH2:30][CH2:29][C:25]2[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=2)[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: O=[N+]([O-])c1c(Cl)nc2c(c1Cl)CCCC2
Reactant: NCCOCCCc1cccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c(Cl)nc2c(c1NCCOCCCc1cccnc1)CCCC2
Temperature: 55 °C
Yield: 94.7 %

Procedure:
A 200 ml round bottom flask was charged with 2,4-dichloro-3-nitro-5,6,7,8-tetrahydroquinoline (10 g, 0.04 mol), triethylamine (6.1 g, 0.06 mol, 1.5 equivalents) and anhydrous N,N-dimethylformamide (100 mL). To this solution was added 2-(3-pyridin-3-ylpropoxy)ethanamine (7.3 g, 0.04 mol). The reaction mixture was heated to 55° C. and maintained overnight with stirring. The reaction was quenched by pouring into water (1000 mL). The reaction mixture was then extracted with a 1:1 solution of hexane/ethyl acetate (4×200 mL). The organics were combined, washed with brine (300 mL) and concentrated to provide 2-chloro-3-nitro-N-[2-(3-pyridin-3-ylpropoxy)ethyl]-5,6,7,8-tetrahydroquinolin-4-amine as an orange syrup (14.8 g, 94%). TLC (10% MeOH/CH2CL2, Rf=0.84).